The Breast Cancer Family Registry (BCFR) Cohort is a large and well-characterized international cohort of multi-generational families that has been created for interdisciplinary collaborative research. Established in 1995 at six sites across the US, Canada and Australia, we recruited and followed 40,029 individuals (33,037 women and 6,992 men) from 15,056 families across the full spectrum of familial risk and/or genetic predisposition. Through recruitment of multiple family members across generations, the BCFR Cohort is unique from other cohorts of unrelated individuals, and has a wide range of absolute breast cancer risk, which enables investigation of factors that modify breast cancer susceptibility and outcomes after diagnosis across the spectrum of risk. The BCFR Cohort is also unique for its comprehensive biospecimen resources, including cell lines for many participants complementing standard stored DNA, plasma and tissue samples. We have followed individuals who were unaffected (n=27,671) and affected (n=12,358) with breast cancer at baseline for up to 25 years (average length of follow-up = 15.2 and 16.1 years, respectively) and prospectively ascertained 879 incident breast cancers and 863 second breast events, respectively. The overarching goal of this application is to enrich the BCFR Cohort by building upon and enhancing the core infrastructure using long-term prospective data collection and measurement of key markers to address novel hypotheses in cancer etiology, survival and survivorship. We aim to answer questions on the role of life course accumulation of risk, critical windows of exposure, and the factors underling the increase in breast cancer incidence in young women. We propose to continue a systematic and coordinated approach across all six sites over the next five years to: 1) enhance the BCFR Cohort by enrolling young women aged 18?39 years who are relatives of enrolled family members and collecting detailed data on menstrual cycles, hormone exposure and physical activity using mobile app technology; 2) retain and follow currently enrolled members of the BCFR Cohort through another wave of follow-up questionnaires, and linkages to cancer and death registries; 3) create a big data repository of multiple ?omics? datasets (e.g., whole genome, serial digital mammograms); and 4) expand the biospecimen resources, including collection of tissue and repeat blood samples. These activities will include collection and updating of detailed risk factor, biospecimen, clinical, and outcome data through novel approaches and technology (e.g., mobile app technologies, optical spectroscopy) and big data approaches. With the addition of these components, we will continue to provide the research community an important and unique family cohort to address cutting-edge research questions of clinical importance on cancer susceptibility, survival and survivorship (e.g., risk assessment, identification of early detection markers, knowledge and perception of risk). Through this resource, we envision a large platform for translational research that will provide rigorous evidence on complex questions related to primary, secondary and tertiary prevention efforts.